title: A novel function for proSAAS as an amyloid anti-aggregant in Alzheimer's disease.
abstract: Neurodegenerative diseases such as Alzheimer's disease (AD) are characterized by an abnormal aggregation of misfolded beta-sheet rich proteins such as β-amyloid (Aβ). Various ubiquitously expressed molecular chaperones control the correct folding of cellular proteins and prevent the accumulation of harmful species. We here describe a novel anti-aggregant chaperone function for the neuroendocrine protein proSAAS, an abundant secretory polypeptide that is widely expressed within neural and endocrine tissues and which has previously been associated with neurodegenerative disease in various proteomics studies. In the brains of 12-month-old APdE9 mice, and in the cortex of a human AD-affected brain, proSAAS immunoreactivity was highly colocalized with amyloid pathology. Immunoreactive proSAAS co-immunoprecipitated with Aβ immunoreactivity in lysates from APdE9 mouse brains. In vitro, proSAAS efficiently prevented the fibrillation of Aβ(1-42) at molar ratios of 1 : 10, and this anti-aggregation effect was dose dependent. Structure-function studies showed that residues 97-180 were sufficient for the anti-aggregation function against Aβ. Finally, inclusion of recombinant proSAAS in the medium of Neuro2a cells, as well as lentiviral-mediated proSAAS over-expression, blocked the neurocytotoxic effect of Aβ(1-42) in Neuro2a cells. Taken together, our results suggest that proSAAS may play a role in Alzheimer's disease pathology.
authors.affiliation: Department of Anatomy and Neurobiology, University of Maryland-Baltimore, Baltimore, Maryland, USA.
authors.forename: Akina
authors.initials: A
authors.lastname: Hoshino
authors.forename: Michael
authors.initials: M
authors.lastname: Helwig
authors.forename: Sina
authors.initials: S
authors.lastname: Rezaei
authors.forename: Casey
authors.initials: C
authors.lastname: Berridge
authors.forename: Jason L
authors.initials: JL
authors.lastname: Eriksen
authors.forename: Iris
authors.initials: I
authors.lastname: Lindberg
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D000682:Amyloid / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry / Q000494:pharmacology; D016707:Tissue Fixation
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C112832:Pcsk1n protein, mouse; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; chaperone; proSAAS; protein aggregation